Mechanisms of mast cell directed carbon nanotube toxicity

肥大细胞定向碳纳米管毒性机制

基本信息

批准号：
9265096
负责人：
Jared Michael Brown
金额：
$ 42.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-10 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265096
关键词：
Address Allergens Allergic Allergic Disease Asthma Biophysics Carbon Nanotubes Cardiovascular system Cell Degranulation Cell Surface Receptors Charge Chemicals Data Defect Dermatitis Development Dose Engineering Excision Funding Agency Genetic Grant Health Hybrids Immune response Immunology In Vitro Inbred Strains Mice Inbreeding Investigation Lead Libraries Lung Mediating Medicine Metals Mission Modeling Mouse Strains Mus Nanotechnology National Institute of Environmental Health Sciences Nature Occupational Exposure Outcome Pathway interactions Pharmacologic Substance Policy Maker Polygenic Traits Process Production Property Proteins Recombinant Inbred Strain Research Risk Assessment Role SR-BI receptor Safety Science Serum Proteins Shapes Signal Pathway Signal Transduction Silver Site Societies Sustainable Development Technology Testing Toxic effect Toxicogenetics Work allergic response base combinatorial compliance behavior consumer product density design genome wide association study mast cell materials science metallicity nano nanomaterials nanomedicine nanoparticle nanotherapeutic novel pathogen physical property prevent protein E public health relevance response safety engineering screening titanium dioxide tool transcriptome sequencing transcriptomics uptake

项目摘要

DESCRIPTION (provided by applicant): Engineered nanomaterials (ENMs) have unique physicochemical properties with potential to impact diverse aspects of society. While the research and proposed applications of ENMs continue to grow rapidly, the health and safety of ENMs still remains a major concern to the public as well as to policy makers and funding agencies. While there has been considerable investigation into the properties of ENMs that elicit toxicity, little work has focused on the ability of ENMs to promote or exacerbate allergic disease. Mast cell activation, which is central to development of allergic disease, has been an impediment to a number of pharmaceuticals and will likely represent a challenge for nanomedicines. Consequently, research on the health and safety implications of ENMs must address the potential for nanomedicines, nano-based consumer products or occupational exposures and the impact on initiation of allergic disease or exacerbation of underlying allergic diseases such as asthma. We have established, through the first cycle of this grant, that certain ENMs elicit mast cell activation either directly (via scavenger receptor B1) or indirectly (via IL-33) leading to adverse pulmonary and cardiovascular outcomes. Based on these findings, we have begun to investigate the properties of ENMs that promote mast cell degranulation or IL-33 production. Our preliminary data has suggested that the density of states or electronic energy levels of the ENM, as a yet unrecognized physicochemical property, contribute to mast cell degranulation through charge transfer to cell surface receptors or proteins. In addition, through preliminary studies, we have found that mast cell responses to ENMs are significantly variable across strains of inbred mice suggesting these responses are polygenic in nature. For this project, we hypothesize that ENM-directed mast cell activation is driven by key physical properties and chemical process at the nano-bio interface, which initiate novel signaling pathways, distinct from other pathogens/bulk allergens, driven by scavenger receptor B1 and this response is largely influenced by genetics. Our objectives are: 1) determine the ENM physicochemical properties responsible for mast cell activation through use of combinatorial library of ENMs; 2) establish the contribution of novel signaling pathways mediated through scavenger receptor B1 in the mast cell response to ENMs through cellular signaling studies; 3) elucidate the role of genetics in mast cell responses to ENM exposure using genome wide association analysis and transcriptomics with a hybrid mouse diversity panel of inbred and recombinant inbred strains. Understanding these mechanisms will allow us to design better models and in vitro screening tools to predict ENM toxicity, which will be important for risk assessment. More importantly, by gaining a more in depth understanding of the physicochemical properties that lead to mast cell degranulation, we will be able to engineer materials to prevent mast cell responses.

描述（由应用程序提供）：工程纳米材料（ENM）具有独特的物理特性，具有影响社会潜水员方面的潜力。尽管ENM的研究和拟议的应用继续迅速增长，但ENM的健康和安全仍然是公众以及政策制定者和资助机构的主要关注点。尽管引起毒性的ENM的属性已经进行了大量投资，但很少有工作集中在ENM促进或加剧过敏性疾病的能力上。肥大细胞激活是过敏性疾病发展的核心，一直是许多药物的障碍，可能代表纳米医学的挑战。因此，对ENM的健康和安全意义的研究必须解决纳米医学，基于纳米的消费产品或发生暴露的潜力，以及对过敏性疾病的倡议的影响或加剧基本的过敏性疾病，例如哮喘。通过该赠款的第一个循环，我们确定了某些ENM会直接（通过清除剂受体B1）或间接（通过IL-33）引起肥大细胞激活，从而导致不良的肺和心血管结局。基于这些发现，我们开始研究促进肥大细胞脱粒或IL-33产生的ENM的性质。我们的初步数据已经提出，作为尚未识别的物理特性，ENM的状态或电子能级的密度通过电荷转移到细胞表面受体或蛋白质来导致肥大细胞的脱粒。此外，通过初步研究，我们发现肥大细胞对ENM的反应在近交小鼠的菌株之间存在显着变化，这表明这些反应本质上是多基因的。对于这个项目，我们假设ENM指导的肥大细胞激活是由纳米生物生物界面的关键物理特性和化学过程驱动的，纳米生物生物界面启动了新型信号通路，这与其他病原体/散装过敏原不同，这是由自动vavenger接收器B1驱动的，并且这种反应在很大程度上受到遗传学的影响。我们的目标是：1）确定通过使用ENMS组合库来确定负责桅杆细胞激活的ENM物理属性； 2）通过细胞信号传导研究，在肥大细胞对ENM的反应中通过清道夫接收器B1介导的新型信号通路的贡献； 3）使用基因组广泛的关联分析和转录组学与杂交和重组近交菌株的混合小鼠多样性面板，阐明了遗传学在肥大细胞对ENM暴露的作用。了解这些机制将使我们能够设计更好的模型和体外筛查工具来预测ENM毒性，这对于风险评估非常重要。更重要的是，通过对导致肥大细胞脱粒的物理特性的深入了解，我们将能够设计材料以防止肥大细胞反应。